This application addresses broad Challenge Area (03) Biomarker Discovery and Validation and specific Challenge Topic Identify and validate clinically relevant, quantifiable biomarkers of diagnostic and therapeutic responses for blood, vascular, cardiac, and respiratory tract dysfunction (03-HL-101 and 03-AG- 112). Septic shock is a major public health problem in both adults and children. Septic shock is a heterogeneous syndrome with the potential to negatively affect virtually all organ systems relevant to this challenge topic: blood (coagulopathy), vascular (distributive shock), cardiac (cardiogenic shock), and respiratory (acute respiratory distress syndrome) function. As such, septic shock has highly variable expression in a given patient cohort. We propose that a key challenge in the field is to reduce and manage this heterogeneity by more effectively stratifying patients for the purposes of more rational and effective clinical research and clinical management. A multi-biomarker-based stratification system has tremendous potential as a clinically feasible and effective strategy for meeting this challenge, as has been done in the field of cancer. Accordingly, we are proposing to derive the pediatric sepsis biomarker risk model (heretofore called PERSEVERE: PEdiatRic SEpsis biomarkEr Risk modEl). PERSEVERE will be based on 15 candidate biomarkers, which have been selected from our own large microarray data set of children with septic shock. The selection process for the candidate biomarkers is systematic and almost completely unbiased. Importantly, all of the candidate biomarkers have biological plausibility and can be readily measured in the blood compartment. We propose to derive PERSEVERE in a learning / derivation cohort of 216 children with septic shock that already exists, based on blood samples obtained within 24 hours of admission to the pediatric intensive care unit with septic shock. After derivation, PERSEVERE will be validated in a prospectively enrolled cohort of 200 children with septic shock. The expected deliverable from this application is a multi-biomarker pediatric sepsis risk model (PERSEVERE) that will allow for outcome prediction and stratification at a clinically relevant time point. PERSEVERE will have a major positive influence on the future conduct of clinical trials targeted at the pediatric septic shock population and in the application of high risk therapies for individual patients with septic shock. In addition, we will have a potential major influence on the adult septic shock population by having the opportunity to test and calibrate PERSEVERE in adults. The deliverable of this program will be a multi-biomarker-based risk model for pediatric septic shock. Child health will be positively impacted by developing the capability to more effectively stratify patients for interventional clinical trials and for the application of high risk therapies in children with septic shock.